The present invention relates to a series of benzimidazole compounds having hypoglycemic, anti-diabetic, anti-cataract and 5-lipoxygenase inhibitory activities, the ability to inhibit the formation of lipid peroxide and related activities, as described in more detail hereafter, and provides processes for their preparation and methods and compositions for their use.
Insulin and sulfonylurea compounds, including tolbutamide and glipizide, have been used for the treatment of diabetes mellitus and hyperglycemia. More recently, it has been discovered that compounds which, like those of the present invention, contain, inter alia, a thiazolidinedione, oxazolidinedione or related group attached, via a methylene or methylidene group, to a benzene ring have this type of activity, and have been proposed for the treatment of non-insulin-dependent diabetes mellitus.
(1) Many thiazolidine derivatives have been reported to have hypoglycemic activity, for example those described in: European Patent Publication No. 008203; European Patent Publication No. 139421; Chem. Pharm. Bull. 30, 3580-3600 (1982) by Y. Kawamatsu et al.; and in European Patent Publication No. 0441605.
(2) Compounds containing heterocyclic ring groups are disclosed in, for example: European Patent Publication No. 208420; European Patent Publication No. 528734; WO 92/07850A; WO 92/07839A; European Patent Publication No. 177353; European Patent Publication No. 306228; and European Patent Publication No. 356214.
(3) Oxazolidine-2,4-dione compounds having hypoglycemic activity are disclosed in, for example: WO 91/07107A; and WO 92/02520A.
(4) In addition, compounds containing an N-hydroxyureido group or a 3,5-dioxooxadiazolidin-2-ylmethylphenyl group and having this type of activity are disclosed in WO 92/03425A.
However, these compounds have a number of disadvantages, for example, their activity is inadequate or there are problems with their safety. Stronger and safer preventive and/or therapeutic agents for these diseases are therefore desired in practice.
The relationship between thiazolidine derivatives and various diseases is described in the following literature:
The effect of thiazolidine compounds on hyperglycemia has been reported in Diabetes 32(9), 804-810 (1983); Diabetes 37(11), 1549-1558 (1988); Prog. Clin. Biol. Res. 265, 177-192 (1988); Metabolism 37(3), 276-280 (1988); Arzneimittelforschung 40(1), 37-42 (1990); Arzneimittelforschung 40(2 Pt 1), 156-162 (1990); and Arzneimittelforschung 40(3), 263-267 (1990).
The effect of thiazolidine compounds on hyperlipidemia has been reported in Diabetes 40(12), 1669-1674 (1991); Am. J. Physiol. 267(1 Pt 1), E95-E101 (1994); and Diabetes 43(10), 1203-1210 (1994).
The effect of thiazolidine compounds on impaired glucose tolerance and insulin resistance has been reported in Arzneimittelforschung 40(2 Pt 1), 156-162 (1990); Metabolism 40(10), 1025-1230 (1991); Diabetes 43(2), 204-211 (1994); and N. Engl. J. Med. 331(18), 1226-1227 (1994).
The effect of thiazolidine compounds on hypertension has been reported in Metabolism 42(1), 75-80 (1993); Am. J. Physiol. 265 (4 Pt 2), R726-R732 (1993); and Diabetes 43(2), 204-211 (1994).
The effect of thiazolidine compounds on cachexia has been reported in Endocrinology 135(5), 2279-2282 (1994); and Endocrinology 136(4), 1474-1481 (1995).
The effect of thiazolidine compounds on nephropathy has been reported in the Journal of Japan Diabetes Society 38, Extra number (1995).
The effect of thiazolidine compounds on coronary artery diseases has been reported in Am. J. Physiol. 265(4 Pt 2), R726-R732 (1993); and Hypertension 24(2), 170-175 (1994).
The effect of thiazolidine compounds on arteriosclerosis has been reported in Am. J. Physiol. 265(4 Pt 2), R726-R732 (1993).
In addition, a high risk of diabetic occurrence has recently been reported in normal persons who have insulin resistance which is not accompanied by impaired glucose tolerance in other words, insulin resistant non-IGT (NGT)! in N. Engl. J. Med. 331(18), 1226-1227 (1994). This fact suggests that an agent which can improve insulin resistance may be useful for the prevention of such diabetic occurrence in normal persons.
We have now discovered that the inclusion in such compounds of certain specific bicyclic nitrogen-containing ring systems results in compounds of much improved activity.